Nanofibrous self-gelling microspheres for heart regeneration Cardiovascular disease (CVD) is the leading cause of death in the world today. In particular, myocardial infarction (MI), commonly known as heart attack, results in permanent heart muscle damage or death, and is the number one killer of heart patients. One major challenge to heart functional recovery after MI is the harsh environment of infarcted areas, which prevents either repopulation of endogenous cells or/and retention/integration of transplanted cells. We have developed injectable nanofibrous self-gelling microspheres as a novel cell carrier and found they dramatically increase cell engraftment in infarcted hearts. We have also developed novel technology for controlled release of biomolecules to enhance heart regeneration. In addition, we have discovered that an epigenetic drug valproic acid (VPA) reduces ~50% of the infarct size when administrated after ischemia reperfusion (IR) and preserves the pumping function of heart in a rat MI model. We therefore hypothesize that high retention of transplanted cells and a reviving epigenetic microenvironment for them can synergize cardiac muscle regeneration in infarcted heart, substantially improving functional recovery. The following specific aims are proposed to test our hypothesis and develop novel regenerative heart therapy: Aim 1. Determine the molecular mechanism of VPA in enhancing cell survival in infarcted heart. Aim 2. Develop nanofibrous self-gelling microspheres as a carrier for cells and biomolecules. Aim 3. Regenerate infarcted heart using VPA and cell-carrying nanofibrous self-gelling microspheres in immunodeficient rats. By accomplishing these specific aims, we will achieve substantial new mechanistic understandings and will develop novel and advanced technologies for heart regeneration.